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PDBsum entry 3qtq

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protein ligands links
Transferase/transferase inhibitor PDB id
3qtq
Jmol
Contents
Protein chain
294 a.a.
Ligands
EDO
X35
Waters ×163
PDB id:
3qtq
Name: Transferase/transferase inhibitor
Title: Cdk2 in complex with inhibitor rc-1-137
Structure: Cyclin-dependent kinase 2. Chain: a. Synonym: cdk2, cell division protein kinase 2, p33 protein engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.204     R-free:   0.233
Authors: S.Betzi,R.Alam,H.Han,A.Becker,E.Schonbrunn
Key ref: E.Schonbrunn et al. (2013). Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. J Med Chem, 56, 3768-3782. PubMed id: 23600925 DOI: 10.1021/jm301234k
Date:
23-Feb-11     Release date:   31-Oct-12    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
294 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm301234k J Med Chem 56:3768-3782 (2013)
PubMed id: 23600925  
 
 
Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.
E.Schonbrunn, S.Betzi, R.Alam, M.P.Martin, A.Becker, H.Han, R.Francis, R.Chakrasali, S.Jakkaraj, A.Kazi, S.M.Sebti, C.L.Cubitt, A.W.Gebhard, L.A.Hazlehurst, J.S.Tash, G.I.Georg.
 
  ABSTRACT  
 
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.